Bronchodilators

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Bronchodilators

• Dr S Mathijs

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Efferent pathway

• Parasympathetic nerves mediate bronchial
  constriction and mucous secretion through action
  on M3 receptors
• Sympathetic nerves innervate blood vessels and
  glands, but not airway smooth muscle
• Circulating adrenaline acts on ß2 adrenoreceptors
  to relax airway smooth muscle
• Main neurotransmitter causing relaxation of
  airway smooth muscle is the NANC inhibitory
  transmitter, nitric oxide
• NANC excitatory transmitters are peptides
  released from sensory neurons

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Asthma
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Pathophysiology

• Wheezing , cough,
• difficulty in expiration
• Reversible airway obstruction
• Constriction of bronchial smooth muscle
• Oedema of mucosa lining small bronchi
• Viscous mucous plug and inflammatory cells
  (eosinophils, T cells and cytokines)
• Inflammatory mediators histamine, serotonin,
  prostaglandin, platelet activating factor (PAF),
  neuropeptides, tachykinins

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Diagnosis in adults

• Hx and exam
• Spirometry to assess presence and severity of
  airflow obstruction
• If pt has high probability of asthma trial of
  treatment
• If pt has low probability investigate

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High probability

• More than one of the following symptoms wheeze,
  breathlessness, cough, chest tightness
• Esp if symptoms worse at night and early morning
• Symptoms in response to exercise, allergen
  exposure, cold air
• Symptoms after taking aspirin or BB
• History of atopic disorder
• Family History
• Wheezing on auscultation
• Low FEV1/PEF
• Otherwise unexplained peripheral blood
  eosinophilia

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Low probability

• Dizziness, light-headed, peripheral tingling
• Chronic productive cough, in absence of wheeze or
  breathlessness
• Normal exam if symptomatic
• Voice disturbance
• Symptoms with cold only
• Hx of smoking
• Cardiac disease
• Normal PEF or spirometry when symptomatic

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Classification of asthma
Intermittent Persistent
Mild Moderate Severe
Category I II III IV
Daytime symptoms lt2/week 3-4 week gt4 /week Continuous
Nocturnal symptoms lt 1/month 2-4/month gt4/month Frequent
PEFR (predicted) gt80 gt80 60-80 lt60
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Goals of treatment

• Reduce morbidity and mortality
• Reduce exacerbations
• Improve quality of life
• Maintain lung functions
• Prevent airway remodeling
• Minimize costs and side effects
• Optimize compliance

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Asthma control

• No daytime symptoms
• No night awakenings due to asthma
• No need for rescue medication
• No limitation on activity including exercise
• Normal lung functions

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Treatment classification
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British Guideline on Management of Asthma,
revised January 2012
Mild Intermittent Preventer Rx Add on Rx Persistent poor control No control
Inhaled short acting ß2 agonist use as needed Inhaled steroids 200-800 µg/d Add long acting ß2agonist (LABA) ?steroids -800 µg/d SR Theophylline Leukotriene modifier ?Steroid 2000 µg/d Add other drugs prn Oral steroids Add other drugs prn
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Stepwise approach

• Start treatment at step most appropriate to
  initial severity
• Achieve early control
• Maintain control by stepping up Rx as necessary
  or step down when control is good
• Before initiating new treatment check compliance
  with existing therapy, inhaler technique and
  eliminate trigger factors
• Consider reductions every 3 months

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Exercise induced asthma

• Leukotriene receptor antagonists
• Long acting ß2 agonists
• Cromolyns
• Oral ß2 agonists
• Theophyllines

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Inhaler devices

• Prescribe inhalers only after pt has received
  training
• Treat with pMDI
• pMDI and spacer
• If ineffective use nebulizer
• Alternative should be found if pt cannot use
  device satisfactory

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Acute exacerbations
Category PEFR ( of best/predicted)
Uncontrolled 50-80
Acute severe 35-50
Life threatening lt35
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Life threatening asthma

• PEF lt 33 best or predicted
• SpO2 lt 92
• PaO2 lt8kPa
• Normal PaCO2
• Silent chest
• Cyanosis
• Poor respiratory effort
• Arrhythmias
• Exhaustion
• Altered level of consciousness

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Management

• Assess severity
• Oxygen
• Corticosteroids
• Nebulized ß2 agonists
• Nebulized Ipratropium bromide
• Consider IVI Aminophylline
• Magnesium Sulphate
• Antibiotics as needed
• Adequate hydration
• If severe- Adrenaline inhalation or subcutaneous
• Intubate and ventilate

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COPD

• Slow progressive airflow limitation
• Partially reversible
• Associated with lung hyperinflation and systemic
  effects
• FEV1/FVC lt70
• FEV1 lt80 of predicted

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Distinguishing COPD and asthma
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Goals of management of COPD

• Recognition of disease
• Prevention of disease progression
• Alleviation of breathlessness and improvement in
  effort tolerance
• Pulmonary rehabilitation and education
• Prevention and treatment of exacerbations
• Prevention and treatment of complications
• Reduction in mortality

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Adapted from GOLD Pocket guide to COPD diagnosis,
management and prevention. Medical
Communications Resources, Inc.2008.
Stage Prevention Bronchodilators Other drugs Other measures
1 Stop smoking
2 As above Inhaled short acting ß2 agonist Inhaled anticholinergics
3 As above Short or long acting bronchodilators Oral Theophylline Trial of inhaled C/S Influenza vaccination Rehab
4 As above As above As above Home O2 Rx Cx
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COPD Rx

• Bronchodilators are mainstay of Rx
• Improve dyspnoea
• Anticholinergic agent most effective in COPD-
  vagal cholinergic tone reversible element
• Anticholinergic agents improve FEV and PEFR
• Reduce exacerbations and hospitalizations
• Inhaled c/s in pt with frequent symptoms,
  frequent exacerbations (2 or more requiring A/B
  and oral steroids in 12 months) and FEV lt50

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ß2 agonists- Mechanism of action

• Change in G protein
• G protein stimulates adenyl cyclase
• cAMP activates protein kinase,
• enzyme responsible for transferring
• phosphate groups from ATP
• to cellular target proteins
• Decrease in calcium ions in cytosol,
• by their uptake into the sarcoplasmic
• reticulum smooth muscle relaxation

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Effects

1. Relaxes smooth muscle bronchi, uterus
2. Inhibits release of inflammatory mediators
3. Improves mucociliary clearance
4. Positive inotropic and chronotropic
5. Vasodilatation in muscle
6. Muscle tremor
7. Hypokalaemia
8. Increased free fatty acid concentration
9. Hyperglycaemia

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Short acting ß2 agonists

• Salbutamol, Fenoterol, Terbutaline
• Work within 15-30 minutes
• Peak 30 -60 minutes
• Relief for 4-6 hours
• Metered dose inhaler via spacer
• Dry powder
• Nebulizer
• Symptomatic relief
• Use as needed
• No change to disease

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Long acting ß2 agonists

• Salmeterol, Formoterol
• Onset of action 1-2 hours
• Duration 12 hours
• Reduces need for additional bronchodilators
• Improves lung functions
• Reduces exacerbation rate
• Combination with long acting anticholinergic
  agents very effective in COPD but very expensive

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Kinetics

• 90 of dose is swallowed, 10-15 of inhaled drug
  remains as free drug in airway
• Plasma elimination t½ 2-4 hours
• Presystemic elimination in intestinal mucosa
• Hepatic conjugation, inactive metabolite excreted
  in urine

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Anticholinergic agents

• Muscarinic 3 receptors in glands and smooth
  muscle.
• Ach enhances movement of calcium ions
• intracellularly, increasing secretions
• At neuromuscular junction,
• membrane of ganglia and
• smooth muscle become more
• permeable for Na ions during
• depolarization, increasing muscle tone
• Parasympathetic nervous system
• has tonic bronchoconstricting action in lungs.
• Muscarinic receptor antagonists have a
  bronchodilatory action.

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Short acting anticholinergics

• Ipratropium
• Onset of action 30-60 minutes
• Duration 3-6 hours
• 3-4 times a day
• Longer duration of action than ß2 agonists
• Metered dose
• Nebulizer

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Long acting anticholinergics

• Tiotropium
• Onset of action 30-60 minutes
• Duration 24-72 hours
• Once daily dosing
• Elimination half life5-6 days

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Side effects

• Dry mouth, bitter taste
• Urinary retention in pt with prostate hypertrophy
• Glaucoma
• Paradoxical bronchoconstriction due to
  sensitivity to preservative

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Methylxanthines

• Inhibit phosphodiesterase
• ?cAMP- relaxes smooth muscle and inhibit mediator
  release from mast cells
• Antagonists of Adenosine at A2 receptors
• Anti inflammatory activity on T-lymphocytes by ?
  release of PAF

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Drugs

• Theophylline per os
• Aminophylline infusion loading dose followed by
  maintenance
• No loading dose required if pt on oral
  Theophylline
• Halve maintenance dose in pt with cirrhosis, CCF,
  or those on AB

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Kinetics

• Narrow therapeutic index must monitor levels
• Metabolized in liver drug interactions!
• Metabolism inhibited by Erythromycin, Cimetidine,
  Fluoroquinolones
• Metabolism induced by Rifampicin
• Avoid in 3rd trimester- neonatal irritability and
  apnoea

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Side effects

• CNS headaches, anxiety, insomnia
• GIT NV
• CVS tachycardia, arrhythmias
• Hypokalaemia
• Dilation of vascular smooth muscle
• flushing, low BP
• Increased risk of convulsions if given with A/B
  that lower seizure threshold (quinolones)

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Corticosteroids Mech of action

• At steroid sensitive tissue there is a specific
  corticosteroid binding protein receptor in
  cytoplasm
• Steroid will activate the receptor exposing a
  DNA binding domain- moves to nucleus and
  steroid-receptor-protein complex binds with DNA
• Increase in RNA polymerase activity, forming
  specific messenger RNA
• Polypeptide synthesis- lipocortin- inhibitor of
  phospholipase A2
• Inhibits PAF, TNFa, prostaglandins, and
  leukotrienes
• Reduction in proliferation of T cells and
  migration of inflammatory cells
• Cell mediated immunity is impaired and antibody
  production suppressed

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Drugs

• Oral Prednisone, Prednisolone
• IVI Hydrocortisone
• Aerosol Budesonide, Beclometasone, Fluticasone
• Nebulizer
• Space devices
• Metered dose inhalers
• Dry powders

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Kinetics

• Inhalational devices deliver 20 of administered
  dose to lungs
• Rest swallowed
• Budesonide and Fluticasone undergo presystemic
  elimination, few systemic side effects

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Side effects

• Candida of pharynx/larynx- use spacer device or
  gargle with mouthwash
• Hoarse voice due to laryngeal myopathy
• at high doses (reversible)
• Depression of adrenal function
• at high doses
• Bruising/skin atrophy
• Inhibits long bone growth/
• Cataracts
• Cushings

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Sodium cromoglicate/ Nedocromil

• Inhibit release of mediators from sensitized mast
  cells
• Prevents exercise induced asthma
• Prophylaxis for allergic asthma in children
• Inhaled powder 10 reaches alveoli
• Little systemic absorption
• Nausea and headaches

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Leukotriene modulators

• 5 lipoxygenase inhibitor Zileuton
• Leukotriene receptor antagonist Montelukast,
  Zafirlukast
• Leukotrienes involved in
• Bronchoconstriction
• Attraction of eosinophils
• Production of oedema

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Leukotriene receptor antagonists

• Competitive inhibition of LTD4, LTC4 at Cys LT1
  receptor
• Reduces steroid requirement
• Improves symptoms in chronic asthma
• Prophylaxis in exercise induced asthma
• Aspirin sensitive asthma

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Side effects

• GIT upset
• Drowsiness take at night
• Fever, rash, arthralgia
• Raised serum transaminase

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Omalizumab

• Recombinant humanized IgE, monoclonal Anti IgE
  antibody
• Given in severe persistent allergic asthma due to
  IgE mediated sensitivity to inhaled allergens
• Asthma not controlled by steroids and LABA
• Binds to IgE at same isotope on Fc region that
  binds FcRI cannot react with IgE already bound
  to mast cells /basophils
• 80-90 reduction in free IgE

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Omalizumab

• Given subcut every 2-4 weeks
• Very expensive
• SE
• Rash
• Urticaria
• Sinusitis
• GIT SE
• Injection site reaction
• Malignancies

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Ketotifen

• Antihistamine
• Stabilizes mast cells
• Inhibit 5 lipoxygenase
• Used in highly allergic children lt 3 years old
  who have atopic eczema and hayfever

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Magnesium sulphate

• Physiological antagonist of calcium-
• smooth muscle relaxation and bronchodilatation
• 2 g IVI over 20 minutes
• Watch out for hypotension
• Hypermagnesaemia
• Muscle weakness/reduced tendon reflexes
• Nausea and flushing
• Slurry speech/double vision
• Rx with Calcium gluconate

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Heliox

• Helium oxygen mixture
• Helium travels more easily down narrowed air
  passages
• Reduces work of breathing , better delivery of
  inhaled bronchodilator
• Under investigation

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Antibiotics in COPD

• Bacteria present in pt with COPD exacerbations
  H.Influenzae, Moraxella Catarrhalis, S.Pneumoniae
• Landmark study
• Treat with antibiotics if pt has 2 out of 3
  symptoms
• Increased cough/sputum production
• Increased dyspnoea
• Increased sputum purulence
• Treat with Amoxicillin/Clavulanic acid,
  Macrolides, Cephalosporins, Doxycycline,
  Fluoroquinolones

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Other drugs in COPD

• Phosphodiesterase inhibitors Roflumilast
  effective in Phase III trials but not yet
  registered
• Mucolytics, cough syrups, acetylcysteine not
  effective and not recommended

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Anaphylaxis
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Allergic manifestations

• Rash, urticaria
• Wheal (swelling) and flare (vasodilatation)
• Anaphylaxis
• BP drops
• Shock
• Glottis oedema
• Bronchospasm
• CVS collapse
• Respiratory distress

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Management of anaphylaxis

• 4 As
• Adrenaline 0.3ml of 1/1000 solution IMI
• Adrenocorticosteroids Hydrocortisone 200-400 mg
  IVI
• Antihistamines Promethazine 25-50 mg IMI or
  slow IVI
• Aminophylline 250 mg slowly IVI

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Allergic rhinitis
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Allergic rhinitis

• Affects over 40 of young adult population
• Prevalence increasing
• Affects social life, school performance and work
  productivity
• Asthma and allergic rhinitis frequently co-exist
  in same subjects

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Pathophysiology

• Inflammation of mucous membrane of nose, eyes,
  eustachian tubes, middle ears, sinuses and
  pharynx
• Triggered by IgE mediated response to an
  extrinsic protein
• Protein binds to IgE on mast cells release of
  mediators histamine, tryptase, chymase, kinins,
  heparin
• Leukotrienes and prostaglandin D2 produced

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Symptoms

• Rhinorrhea
• Secretions ?( mucous glands stimulated)
• Vascular permeability increased plasma exudate
• Vasodilatation congestion and pressure
• Sensory nerves stimulated sneezing and itching
• Systemic effects fatigue, sleepiness, malaise

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Diagnosis Hx

• Perennial/seasonal
• Unilateral complaints polyps, foreign body,
  deviated septum
• Trigger factors
• Response to Rx
• Co-morbid conditions OM, sinusitis, polyps,
  atopic dermatitis, asthma, allergic
  conjunctivitis

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Diagnosis Exam

• Allergic shiners
• Nasal crease allergic salute
• Pale boggy blue gray mucosa of nasal turbinates
• Thin watery secretions
• Septum/polyps
• Ears
• Eyes tears, Dennie Morgan lines, swelling of
  palpebral conjunctivae
• Cobblestoning lymphoid tissue on posterior
  pharynx
• Malocclusion, high arched palate

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Treatment

• Environmental control
• Pharmacological treatment
• Immunotherapy

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Pharmacological Rx

• Intermittent symptoms
• Oral antihistamine
• Decongestants
• Both as needed
• Chronic symptoms
• Intranasal steroid spray
• Other
• Ocular antihistamine drops
• Intranasal antihistamine spray
• Intranasal cromolyn
• Short course of oral steroids in severe, acute
  episode
• Leukotriene receptor antagonists if both
  rhinitis and asthma

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2nd generation antihistamines

• Compete with histamine at H1 receptor in blood
  vessels, GI tract, respiratory tract
• Improve rhinorrhea, sneezing, itching
• No effect on nasal congestion
• Use for seasonal/episodic rhinitis
• Prn/daily
• Combinations with decongestants
• Cetirizine, Desloratadine, Loratadine,
  Fexofenadine

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1st generation antihistamines

• Adverse effects
• Do not use

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Decongestants

• Vasoconstriction by activating a receptors in
  respiratory mucosa
• Pseudoephedrine produces weak bronchial
  relaxation, has no effect on asthma
• Alone/combination with antihistamines
• SE anxiety/insomnia
• Caution CVS disease, HT, hyperthyroidism

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Corticosteroids

• Nasal spray
• Relief of all symptoms
• More effective than monotherapy with
  antihistamine/cromolyn
• Greater benefit if combined with other agents
• Safe, few side effects
• Does not Rx eye symptoms
• Beclomethasone, Budesonide, Fluticasone,
  Mometasone, Triamcinolone

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Intranasal antihistamines

• Intermittent allergic rhinitis
• Azelastine, Levocabastine
• Some effect on nasal congestion
• Vasomotor rhinitis
• 11 of pt- systemic absorption - sedation

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Intranasal cromolyns

• Mast cell stabilization
• No anti-inflammatory effects/antihistamine
  effects
• Effective if used as prophylaxis

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Immunotherapy

• Success rate 80-90 for certain allergens esp
  pollen, dust mites, cat
• Long term treatment 3-5 years
• Desensitization
• Administer with allergen that pt is known to be
  sensitive
• Severe systemic allergy can occur
• Indications
• Severe disease
• Poor response to treatment
• Presence of co-morbid conditions/Complications

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Take home message

• Treat asthma as soon as possible
• Prevent exacerbations
• Screen pt with asthma for allergic rhinitis
• Patient education!!
• Any questions?